Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   38882   clinical trials with a EudraCT protocol, of which   6392   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Print Download

    Summary
    EudraCT Number:2012-003650-88
    Sponsor's Protocol Code Number:BAY94-9343/15743
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-10-30
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2012-003650-88
    A.3Full title of the trial
    A randomized, open-label, active-controlled, Phase II study of intravenous anetumab ravtansine (BAY 94-9343) or vinorelbine in patients with advanced or metastatic malignant pleural mesothelioma overexpressing mesothelin and progressed on first line platinum/pemetrexed-based chemotherapy
    Ensayo Fase II aleatorizado, abierto, controlado con tratamiento activo, de anetumab ravtansina (BAY 94-9343) intravenoso o vinorelbina en pacientes con mesotelioma pleural maligno avanzado o metastásico que sobreexpresen mesotelina y hayan progresado a primera línea de quimioterapia basada en platino/pemetrexed
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study investigating the efficacy and safety of anetumab ravtansine as 2nd line treatment for malignant pleural mesothelioma.
    Ensayo para evaluar la eficacia y seguridad de anetumab ravstanisa como segunda línea de tratamiento para mesotelioma pleural maligno
    A.3.2Name or abbreviated title of the trial where available
    Phase II anetumab ravtansine as 2nd line treatment for malignant pleural mesothelioma (MPM)
    Ensayo Fase II de anetumab ravtansina intravenoso o vinorelbina en pacientes con mesotelioma pleural
    A.4.1Sponsor's protocol code numberBAY94-9343/15743
    A.5.4Other Identifiers
    Name:Mesothelin-ADCNumber:BAY94-9343
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorBayer HealthCare AG
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBayer HealthCare AG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBayer HealthCare AG
    B.5.2Functional name of contact pointBayer Clinical Trials Contact
    B.5.3 Address:
    B.5.3.1Street AddressCTP Team / Ref: "EU CTR" / Bayer Pharma AG
    B.5.3.2Town/ cityBerlin
    B.5.3.3Post code13342
    B.5.3.4CountryGermany
    B.5.4Telephone number0034.900102372
    B.5.6E-mailclinical-trials-contact@bayerhealthcare.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEMA/OD/063/12
    D.3 Description of the IMP
    D.3.1Product nameAnetumab Ravtansine
    D.3.2Product code BAY 94-9343
    D.3.4Pharmaceutical form Lyophilisate for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAnetumab Ravtansine
    D.3.9.3Other descriptive nameBAY 94-9343
    D.3.9.4EV Substance CodeSUB178041
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name NAVELBINE 10mg
    D.2.1.1.2Name of the Marketing Authorisation holderPierre Fabre Pharma
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namevinorelbine
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNVINORELBINE
    D.3.9.1CAS number 71486-22-1
    D.3.9.4EV Substance CodeSUB00069MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name NAVELBINE 50mg
    D.2.1.1.2Name of the Marketing Authorisation holderPierre Fabre Pharma
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namevinorelbine
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNVINORELBINE
    D.3.9.1CAS number 71486-22-1
    D.3.9.4EV Substance CodeSUB00069MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients with advanced or metastatic malignant pleural mesothelioma overexpressing mesothelin
    Pacientes con mesotelioma pleural maligno avanzado o metastásico que sobreexpresen mesotelina
    E.1.1.1Medical condition in easily understood language
    Advanced or metastatic malignant pleural mesothelioma
    Mesotelioma pleural maligno avanzado o metastásico
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level LLT
    E.1.2Classification code 10035605
    E.1.2Term Pleural mesothelioma malignant advanced
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Test the superiority of anetumab ravtansine monotherapy over vinorelbine in progression-free survival (PFS)
    Determinar la superioridad de anetumab ravtansina en monoterapia sobre vinorelbina en la supervivencia libre de progresión (SLP)
    E.2.2Secondary objectives of the trial
    - Test overall survival
    - Evaluate pulmonary function
    - Evaluate patient-reported outcomes ? symptom burden and health-related quality of life (QoL)
    - Evaluate other indicators of treatment efficacy
    - Evaluate safety

    The other objectives of this study are to evaluate the:
    - Pharmacokinetics and immunogenicity
    - Biomarkers
    - Determinar la supervivencia global (SG)
    - Evaluar la función pulmonar
    - Evaluar los resultados comunicados por el paciente (PROs): la carga de los síntomas y la calidad de vida (QoL) relacionada con la salud
    - Evaluar otros indicadores de la eficacia del tratamiento (indicadores de respuesta tumoral)
    - Evaluar la seguridad

    Otros objetivos de este estudio son evaluar:
    - Farmacocinética (FC)
    - Inmunogenicidad
    - Biomarcadores
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Eligibility criteria for mesothelin expression testing:
    1. Written informed consent for mesothelin expression testing.
    2. Unresectable locally advanced or metastatic MPM, confirmed by histology.
    3. Availability of archival or fresh tissue for testing of mesothelin expression level.
    Note: Archival tissue is preferred and fresh biopsy should only be obtained if no archival tissue is available and if in the investigator's judgement, there is no additional risk for the patient?s safety. Patients with a sarcomatoid histology are not expected to have mesothelin overexpression and should not be enrolled in the study.
    4. Age >= 18 years (age limit may be higher if legally required in a country e.g. in Japan adult age is considered > 20 years).
    5. ECOG PS of 0 or 1 (specified in Section 16.1).
    6. Life expectancy of at least 3 months.
    7. No prior treatment with anetumab ravtansine or vinorelbine.
    8. No prior use of targeted agents, experimental therapy or systemic anti-cancer treatment other than ongoing or completed 1st line platinum/pemetrexed (with or without bevacizumab).

    Eligibility criteria for study treatment
    1. Written informed consent for full study.
    2. Histological documentation of malignant pleural mesothelioma overexpressing mesothelin at the 2+ and 3+ level in at least 30% of tumor cells as determined by centrally performed IHC.
    Note: Patients with a sarcomatoid histology are not expected to have mesothelin overexpression and should not be enrolled in the study.
    3. Unresectable locally advanced or metastatic MPM after progression on 1st line treatment with platinum in combination with pemetrexed. Last dose of previous therapy must be at least 4 weeks before start of study treatment.
    Note: Patients progressed on 1st line treatment with platinum plus pemetrexed in combination bevacizumab are allowed
    4. Patients must have at least 1 measurable lesion according to mRECIST for mesothelioma. This will be confirmed by central review of images before the patient can be randomized into the study
    Note: Patients with non-pleural disease as the only relapse site after a pleural surgery (e.g. subcutaneous lesions, nodal lesions, lung lesions etc.) will be eligible if at least 1 measurable lesion according to RECIST 1.1 is present
    5. Age >= 18 years (age limit may be higher if legally required in a country e.g. in Japan adult age is considered > 20 years)
    6. ECOG PS of 0 or 1
    7. Life expectancy of at least 3 months
    8. Women of childbearing potential (WOCBP) and men must agree to use adequate contraception from signing of the ICF for full study until at least 3 months after the last study drug administration. The investigator or a designated associate is requested to advise the patient how to achieve an adequate birth control.9. Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements conducted within 7 days before starting study treatment:
    - Total bilirubin < 1.5 x the upper limit of normal (ULN). Documented Gilbert syndrome is allowed if total bilirubin is mildly elevated (< 6 mg/dL).
    - ALT and AST < 2.5 x ULN (< 5 x ULN for patients with liver involvement of their cancer).
    - ALP limit < 2.5 x ULN (< 5 x ULN for patients with liver involvement of their cancer).
    - Amylase and lipase < 1.5 x ULN.
    - Serum creatinine < 1.5 x ULN
    - Glomerular filtration rate (GFR) >= 30 mL/min/1.73 m2 according to the Modification of Diet in Renal Disease (MDRD) abbreviated formula
    - Adequate coagulation, as assessed by the following laboratory test results:
    o International normalized ratio (INR) or prothrombin time (PT) < 1.5 x ULN (CTCAE Grade < 1)
    o Partial thromboplastin time (PTT) or activated PTT (aPTT) < 1.5 x ULN (CTCAE Grade < 1)
    Note: Patients on anti-coagulation therapy will be allowed to participate if INR / PT and PTT / aPTT test results are compatible with the acceptable benefit-risk ratio at the investigator's discretion
    - Platelet (PLT) count > 100000/mm3 , without PLT transfusion within 3 weeks before the start of study treatment
    - Hemoglobin (Hb) > 9 g/dL, without blood transfusion or erythropoietin within 6 weeks before the start of study treatment
    - Absolute neutrophil count (ANC) > 1500/mm3, without biologic response modifiers, such as G-CSF, within 6 weeks before the start of study treatment
    10. Left ventricular ejection fraction (LVEF) >= the lower limit of normal (LLN) according to local institution ranges of normality.
    Criterios de inclusión para la prueba de expresión de mesotelina:
    1.Consentimiento informado (CI) por escrito para la prueba de expresión de mesotelina.
    2.MPM no resecable metastásico o localmente avanzado, confirmado mediante histología.
    3.Disponibilidad de tejido de archivo o fresco para las pruebas de nivel de expresión de mesotelina.Nota:se prefiere la obtención de tejido de archivo y la muestra de biopsia fresca debe obtenerse únicamente si no se dispone de tejido de archivo disponible y si, según el criterio del investigador, no supone un riesgo añadido para la seguridad del paciente(PAC).No se espera que los PAC con histología sarcomatoide presenten sobreexpresión de mesotelina y no deben incluirse en la preselección.
    4.Edad >=18 años(la edad mínima puede ser mayor si así lo exige la legislación del país participante, p.ej. en Japón la edad adulta se considera >20 años).
    5.Estado Funcional(EF)del ECOG de 0 o 1.
    6.Esperanza de vida de al menos 3 meses.
    7.Ningún tratamiento(TTO)previo con anetumab ravtansina o vinorelbina. 8.PAC que no hayan utilizado previamente FCOs dirigidos, TTO en fase de investigación o TTO antineoplásico sistémico diferente del TTO en curso o finalizado de 1.ª línea con platino/pemetrexed (con o sin bevacizumab).

    Criterios de elegibilidad para el estudio completo
    1.CI por escrito del estudio completo.
    2.Documentación histológica del MPM con sobreexpresión de mesotelina con niveles 2+ y 3+ en al menos el 30 % de las células tumorales, determinado de forma central mediante IHQ.Nota:No se espera que los PAC con histología sarcomatoide presenten sobreexpresión de mesotelina y no deben incluirse en el estudio.
    3.MPM no resecable localmente avanzado o metastásico después de progresión a 1.ª línea de TTO con platino en combinación con pemetrexed. La última dosis del TTO previo tiene que ser al menos de 4 semanas antes del inicio del TTO del estudio. Nota: se permiten PAC que hayan progresado al TTO de 1.ª línea con platino y pemetrexed en combinación con bevacizumab.
    4.Los PAC deben tener al menos una lesión medible según los criterios RECISTm para el mesotelioma. Se confirmará mediante revisión central de las imágenes antes de que el PAC pueda aleatorizarse en el estudio. Nota:los PAC con enfermedad no pleural como único lugar de recidiva después de la cirugía pleural (p.ej. lesiones subcutáneas, lesiones ganglionares, lesiones pulmonares, etc.) serán elegibles si presentan al menos una lesión medible según los criterios RECIST 1.1.
    5.Edad >= 18 años (la edad mínima puede ser mayor si así lo exige la legislación del país participante, p. ej., en Japón la edad adulta se considera > 20 años).
    6.EF del ECOG de 0 o 1.
    7.Esperanza de vida de al menos 3 meses.
    8.Las mujeres y los varones con capacidad reproductora deberán aceptar la adopción de medidas anticonceptivas apropiadas desde la firma del CI para el estudio completo y por lo menos hasta 3 meses después de la última administración del fármaco(FCO) del estudio. El investigador o delegado deberá aconsejar al PAC sobre anticonceptivos altamente eficaces. 9.Función medular, hepática y renal aceptables, según la evaluación de los siguientes parámetros analíticos obtenidos en los 7 días previos al inicio del TTO del estudio: *Bilirrubina total < 1,5 veces el límite superior de la normalidad (LSN). Se permite el síndrome de Gilbert documentado si la bilirrubina total se encuentra ligeramente elevada (< 6 mg/dl).
    *AST y ALT < 2.5 veces el LSN (< 5 veces el LSN en PAC con afectación neoplásica hepática).
    *FA límite <2,5 veces el LSN (< 5 veces el LSN en PAC con afectación neoplásica hepática).
    *Amilasa y lipasa< 1,5 veces el LSN. *Creatinina sérica < 1,5 veces el LSN. *Filtración glomerular (FG) >= 30ml/min/1,73m2 según la fórmula del estudio de modificación de la dieta en la enfermedad renal, Modification of Diet in Renal Disease (MDRD).
    *Coagulación adecuada, evaluada mediante los siguientes resultados analíticos:
    -Cociente internacional normalizado (INR) o tiempo de protrombina (TP) < 1,5 veces el LSN (grado< 1 según los CTCAE).
    -Tiempo de tromboplastina parcial (TTP) o TTP activado (TTPa) < 1,5 veces el LSN (grado< 1 según los CTCAE).Nota:los PAC que estén tomando una dosis estable de TTO anticoagulante podrán participar si las pruebas de INR/TP y TTP/TTPa son compatibles con la relación riesgo/beneficio aceptable, según el criterio del investigador.
    *Plaquetas>100000/mm3 , sin transfusión de plaquetas en las 3 semanas antes del inicio del TTO del estudio. *Hemoglobina (Hb)>9 g/dl, sin transfusión de sangre o eritropoyetina en las 6 semanas previas al inicio del TTO del estudio.
    *Recuento absoluto de neutrófilos (RAN)>1500/mm3, sin modificadores de la respuesta biológica, como G-CSF, en las 6 semanas antes del inicio del FCO del estudio.
    10.Fracción de eyección ventricular izquierda (FEVI)>= límite inferior de la normalidad (LIN) de conformidad con los intervalos de normalidad utilizados en el centro.
    E.4Principal exclusion criteria
    1. Previous assignment to treatment during this study. Patients permanently withdrawn from study participation will not be allowed to re-enter the study.
    2. Previous (within 5 drug half-lifes -if drug half-life in subjects is known- or 28 days, whichever is shorther, before the start of study treatment) or concomitant participation in another clinical study with investigational medicinal product(s).
    3. Close affiliation with the investigational site; e.g. a close relative of the investigator, dependent person (e.g. employee or student of the investigational site).
    4. More than 1 previous systemic anti-cancer therapy line (even if therapy used as neoadjuvant or adjuvant treatment).
    Note: Patients pre-treated with systemic therapy other than platinum, pemetrexed, bevacizumab (e.g. other cytotoxic drugs, immunotherapy, targeted therapy, hormonal therapy, or any other experimental or approved therapy) are not to be enrolled.
    5. Previous or concurrent cancer that is distinct in primary site or histology from mesothelioma within 5 years before randomization.
    Exceptions: curatively treated
    - Cervical cancer in situ.
    - Non-melanoma skin cancer.
    - Superficial bladder tumors [Ta (Non-invasive tumor), Tis (Carcinoma in situ) and T1 (Tumor invades lamina propria)].
    6. Major surgery, open biopsy or significant traumatic injury within 28 days before the start of study treatment.
    7. Pregnant or breast-feeding patients. WOCBP must have a serum pregnancy test performed a maximum of 7 days before the start of study treatment, and a negative result must be documented before the start of study treatment.
    8. Pre-existing cardiac conditions as outlined below:
    - Congestive heart failure > New York Heart Association (NYHA) class 2
    - Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months). Myocardial infarction less than 6 months before the start of study treatment.
    - Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted).
    9. Clinically significant uncontrolled hypertension (systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg despite optimal medical management).
    10. Arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), or pulmonary embolism within 6 months before the start of study treatment; venous thrombotic events as deep vein thrombosis within 3 months before the start of study tretment.
    11. Ongoing or active infection (bacterial, fungal, or viral) of NCI-CTCAE version 4.03 Grade > 2.
    12. Known history of human immunodeficiency virus (HIV) infection.
    13. Known history of chronic hepatitis B or C.
    14. Patients with seizure disorder requiring medication.
    15. Symptomatic brain metastases or meningeal tumors or other uncontrolled metastases in the central nervous system (CNS) unless the patient
    - Is > 6 months from definitive therapy,
    - Has a negative imaging study within 4 weeks before study entry (ICF signature for full study) and
    - Is clinically stable with respect to the tumor at the time of study entry.
    16. History of organ allograft, stem cells or bone marrow transplant.
    17. Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding event > CTCAE Grade 3 within 4 weeks before the start of study treatment.
    18. Non-healing wound, ulcer, or bone fracture.
    19. Renal failure requiring peritoneal or hemodialysis.
    20. Known hypersensitivity to anetumab ravtansine or vinorelbine, study drug classes or excipients in the formulation.
    21. Any illness or medical conditions that are unstable or could jeopardize the safety of the patient and his/her compliance in the study.
    22. Unresolved toxicity higher than NCI-CTCAE version 4.03 Grade 1 attributed to any prior therapy/procedure excluding anemia Grade 2 and alopecia of any Grade.
    23. Any prohibited prior or concomitant therapy
    1.Asignación previa a un tratamiento(TTO) durante este estudio. Los PAC retirados permanentemente de la participación en el estudio no podrán ser readmitidos.
    2.Tratamiento previo (en un plazo de 5 semividas del fármaco, si se conoce la semivida del fármaco en PAC, o 28 días, antes del inicio del TTO del estudio, lo que sea más corto) o participación simultánea en otro estudio clínico con medicamentos en investigación (MI).
    3.Relación estrecha con el centro en el que se realiza la investigación; p. ej., ser familiar próximo del investigador, o bien ser dependiente del centro (es decir, ser empleado o estudiante en el mismo).
    4.Más de una línea de TTO antineoplásico sistémico previo (incluso si el TTO se utiliza como TTO neoadyuvante o adyuvante). Nota: no se incluirán los PAC tratados previamente con TTO sistémico que no sea platino, pemetrexed, bevacizumab (p. ej., otros fármacos citotóxicos, inmunoterapia, terapia dirigida, TTO hormonal o cualquier otro TTO experimental o autorizado).
    5.Cáncer previo o concomitante que sea distinta en la localización primaria o por las características histológicas del mesotelioma en los 5 años antes de la aleatorización.
    Excepciones: tratado de forma curativa:
    *Cáncer de cuello de útero localizado.
    *Cáncer de piel no melanoma.
    *Tumores vesicales superficiales (tumor no invasivo [Ta], carcinoma localizado [Tis] e invasión tumoral de la lámina propia [T1]).
    6.Cirugía mayor, biopsia abierta o traumatismo significativo en un plazo de 28 días antes del inicio del TTO del estudio.
    7.Embarazo o lactancia. En las mujeres potencialmente fértiles deberá realizarse una prueba de embarazo en suero un máximo de 7 días antes del inicio del TTO del estudio y se deberá documentar un resultado negativo antes del inicio del TTO del estudio.
    8.Alteraciones cardíacas preexistentes, tal como se indica a continuación:
    *Insuficiencia cardíaca congestiva de clase > II de la New York Heart Association (NHYA).
    *Angina inestable (síntomas de angina en reposo), angina de nueva aparición (que ha empezado en los últimos 3 meses). Infarto de miocardio menos de 6 meses antes del inicio del TTO del estudio.
    *Arritmias cardíacas que requieran TTO antiarrítmico (los betabloqueantes o la digoxina están permitidos).
    9.Hipertensión no controlada clínicamente significativa (presión arterial sistólica >150mm Hg o presión arterial diastólica >90mm Hg a pesar del TTO médico óptimo).
    10.Acontecimientos embólicos o trombóticos arteriales como accidente cerebrovascular (incluidos accidentes isquémicos transitorios) o embolia pulmonar venosa en los 6 meses antes del inicio del TTO del estudio; acontecimientos trombóticos venosos como trombosis venosa profunda en los 3 meses anteriores al inicio del TTO del estudio.
    11.Infección activa o en curso (bacteriana, fúngica o vírica) de grado>2 según la versión 4.03 de los CTCAE-NCI.
    12.Antecedentes conocidos de infección por el virus de la inmunodeficiencia humana(VIH).
    13.Antecedentes conocidos de hepatitis crónica B o C.
    14.PAC con trastornos convulsivos que requieran medicación.
    15.Metástasis cerebrales sintomáticas o tumores meníngeos u otras metástasis no controladas en el sistema nervioso central (SNC) a menos que el PAC:
    *Lleve>6 meses de TTO definitivo.
    *Presente una prueba de diagnóstico por imagen negativa en las 4 semanas antes de la inclusión en el estudio (firma del CI para el estudio) y
    *esté clínicamente estable con respecto al tumor en el momento del inicio del estudio.
    16.Antecedentes de aloinjerto de órganos, células madre o trasplante de médula ósea.
    17.PAC con signos o antecedentes de diátesis hemorrágica. Cualquier hemorragia o episodio hemorrágico de grado > 3 según los CTCAE en las 4 semanas previas al inicio del TTO del estudio.
    18.Herida tórpida, úlcera sin cicatrizar o fractura ósea no consolidada.
    19.Insuficiencia renal que requiera diálisis peritoneal o hemodiálisis.
    20.Hipersensibilidad conocida a anetumab ravtansina o vinorelbina, clases de los fármacos del estudio o excipientes de la formulación.
    21.Cualquier enfermedad o afección médica que sea inestable o que pueda poner en peligro la seguridad del PAC y su cumplimiento terapéutico en el estudio.
    22.Toxicidad no resuelta de grado mayor a 1 según los CTCAE-NCI versión 4.03, atribuida a cualquier TTO o procedimiento previo, salvo anemia de grado 2 y alopecia de cualquier grado.
    23.Cualquier TTO previo o concomitante prohibido
    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoint is progression free survival.
    El objetivo principal es la supervivencia libre de progresión (SLP)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Assuming median PFS of 3.6 months under vinorelbine treatment and constant hazards and a 2:1 treatment:comparator randomization, a 100% prolongation of PFS in the anetumab
    ravtansine arm in comparison to the comparator arm can be detected at a 1-sided significance level of 0.0125 with 90% power, with a single-stage trial with approximately 117 PFS events (hazard ratio 0.5). Assuming a maximum accrual rate of 10.5 patients/month (17.5 patients/
    month screened with 40% overall screening failure rate) with 8-month linear accrual ramp-up,
    and a 2.7%/month dropout (loss to follow-up and unevaluable for tumor assessment) rate,
    183 patients be will accrued in approximately 20.4 months and reach endpoint maturation of
    117 events in approximately 23.9 months.
    Asumiendo mediana real d la SLP d 3,6meses(MS) n TTO cn vinorelbina y riesgos constantes y proporción d aleatorización 2:1 TTO:comparador,pued dtectarse prolongación dl 100% en SLP n grupo d anetumab ravtansina n comparación cn grupo comparador,n 1nivel d significación unilateral d 0,0125 cn 1potencia dl 90%,n 1ensayo d 1etapa cn aprox. 117casos d SLP(cociente d riesgos instantáneos d 0,5).Asumiendo 1tasa d inclusión máx. d 10,5pacientes(PAC)/mes (17,5PAC/mes seleccionados cn tasa d fracasos d selección global dl 40%) cn 8MS d ascenso lineal acumulado,y tasa d abandonos d 2,7%/mes(pérdida d seguimiento y PAC no evaluables para la evaluación tumoral),se incluirá 1total d 183PAC n aprox. 20,4MS y se alcanza el valor dfinitivo dl criterio d valoración d los 117acontecimientos n 23,9MS
    E.5.2Secondary end point(s)
    The secondary endpoint is overall survival.
    El objetivo secundario es la supervivencia global
    E.5.2.1Timepoint(s) of evaluation of this end point
    Assuming true median OS of 9.6 months under vinorelbine treatment and constant hazards, a 60% prolongation of true OS (median 15.4 months) in the anetumab ravtansine arm in comparison to the comparator arm (median 9.6 months) can be detected with an overall 73% power and an overall 1-sided significance level of 0.025 (hazard ratio 0.625), with a 2-stage group sequential test with a total of 135 events.
    Suponiendo una mediana real de la SG de 9,6 meses en tratamiento con vinorelbina y riesgos constantes, se ha diseñado un análisis de hipótesis secuencial por grupos de 2 etapas con un total de 135 eventos, para detectar un 60 % de prolongación en la SG real (mediana de 15,4 meses) en el grupo con anetumab ravtansina en comparación con el grupo comparador, con una potencia del 73 % y un nivel de significación unilateral de 0,025 (cociente de riesgos instantáneos de 0,625).
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic Yes
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA50
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Belgium
    Canada
    Finland
    France
    Germany
    Italy
    Japan
    Korea, Republic of
    Netherlands
    Poland
    Russian Federation
    Spain
    Turkey
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    For each participating EU country, the end of the study according to the EU Clinical Trial Directive will be reached when the last visit of the last patient for all centers in the respective country has occurred.
    As for this study, important data will be collected after LPLV, the end of the study as a whole will be the date when the clean database is available.
    En cada uno de los países de la UE participantes, y de acuerdo con la Directiva Europea de Ensayos Clínicos, el final del estudio tendrá lugar cuando se haya realizado la última visita al último paciente en todos los centros del país respectivo.
    En cuanto a este estudio, se recogerán datos importantes después de la LPLV, y la finalización del estudio en su conjunto será la fecha en la que se disponga de la base de datos limpia.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 100
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 83
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state13
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 81
    F.4.2.2In the whole clinical trial 183
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-12-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-12-04
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-08-09
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2021 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA